EP0004319B1 - N-(pyridothiénopyrazol) amides, procédé pour leur préparation et compositions pharmaceutiques les contenant - Google Patents

N-(pyridothiénopyrazol) amides, procédé pour leur préparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
EP0004319B1
EP0004319B1 EP79100705A EP79100705A EP0004319B1 EP 0004319 B1 EP0004319 B1 EP 0004319B1 EP 79100705 A EP79100705 A EP 79100705A EP 79100705 A EP79100705 A EP 79100705A EP 0004319 B1 EP0004319 B1 EP 0004319B1
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Prior art keywords
compound
methyl
ethyl
reaction
pyrazolo
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Expired
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EP79100705A
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German (de)
English (en)
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EP0004319A1 (fr
Inventor
Edward Charles Hermann
Joel Gayton Whitney
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EIDP Inc
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EI Du Pont de Nemours and Co
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Priority claimed from US05/970,732 external-priority patent/US4220776A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • This invention is directed to a class of novel compounds, a process for their preparation and pharmaceutical compositions containing them.
  • viruses are intracellular parasites, the functions of which necessarily involve the metabolic processes of the invaded cell. For this reason, agents that inhibit or kill viruses are likely to cause injury to the host cell as well. Thus, the development of effective antiviral agents presents even more difficulty than the search for drugs to combat diseases caused by other microorganisms.
  • the invention is, therefore, directed to a novel class of N-(pyridothienopyrazol)amides which are intended for use in the treatment or prevention of the "common cold", an upper respiratory disease of man characterized by rhinorrhea, nasal congestion, sneezing, pharyngeal discomfort, and cough'. More particularly, these novel compounds are antirhinoviral agents, inhibiting the multiplication of rhinoviruses, the causative agents of most colds. In contrast to drugs used for symptomatic relief of colds, these compounds inhibit the production of the infectious agent, i.e., one or more of the over one- hundred known strains of rhinovirus. Many of these compounds are also active against certain other picornaviruses. In particular, the invention is directed to compounds corresponding to the formula wherein
  • the invention is also directed to pharmaceutical compositions containing the above-described compounds.
  • R 1 be methyl and/or that R 2 be selected from the group consisting of 3-pyridyl, chloroalkyl, and a group in which R 3 and R 4 are independently C 1-3 alkyl and R 5 is H or C 1-5 alkyl. Still further preferred are those compounds in which R 2 is and the R groups are selected from one of the following:
  • the most preferred compounds are: 2,2-diethyl-N-[1-methyl-1H-pyrazolo(3',4':4,5)thieno(2,3-b)pyridin-3-yl]butanamide; and 2-ethyl-N-[1-methyl-1H-pyrazolo(3',4':4,5)thieno(2,3-b)pyridin-3-yl]-hexanamide.
  • the compounds of this invention are made by the following sequence of reactions:
  • R a is a lower (C '-4 ) alkyl group which is preferably methyl or ethyl and MOH is an aqueous alkali metal hydroxide which is preferably potassium hydroxide.
  • Reaction (1) is both a diazotization and diazo salt decomposition reaction which, because of its highly exothermic nature, is preferably carried out at low temperatures with agitation. Preferred temperatures are 0-10°C. However, it will be recognized that the reaction could be carried out at higher temperatures by introducing the reactant at a slower rate in order for the exotherm to become dissipated. In reaction (1), other nitrites may be used to effect diazotization. This reaction step is of particular interest, however, from the standpoint that, by analogy with similar aromatic amines, it would be expected to produce the corresponding hydroxyl compound, not the bromine-substituted material.
  • the starting material for Reaction (1), I is described in J. Het. Chem., 11, 975 (1974).
  • Reaction (2) is a hydrolysis reaction, which can be carried out with either an acid or, as illustrated above, with a base.
  • Preferred bases include NaOH and KOH of which the latter is especially preferred.
  • the hydrolyzed product of Reaction (2) is then converted to 3-bromothieno(2,3-b)pyridine-2-carboxamide.
  • the acid is converted to an acid halide (Reaction 3), which in turn is converted to the corresponding carboxamide by ammonalysis (Reaction 4).
  • the intermediate carboxylic acid halides can be prepared by reaction of the carboxylic acid with inorganic halides such as thionyl chloride or alternatively by reaction of the carboxylic acid or alkali metal salt with oxalyl chloride or bromide.
  • Mixed anhydrides of the carboxylic acid can be prepared with alkyl chloroformates, and subsequently converted to the amide.
  • ethyl 3-bromothieno(2,3-)pyridine-2-carboxylate could be transformed directly to the corresponding carboxamide by ammonolysis, as follows:
  • Reaction (5) is a dehydration step by which 3-bromothieno(2,3-b)pyridine-2-carboxamide is converted to the corresponding carbonitrile.
  • a preferred reagent for this purpose is POC1 3 .
  • carboxylic acid can be reacted with chlorosulfonyl isocyanate to form the carbonitrile directly as follows:
  • Reaction (6) the above-described 2-carbonitrile compound (VI) is reacted with methyl- or ethyl-hydrazine in solution to form 1-methyl- or 1-ethyl-1 H-pyrazolo(3',4':4,5)thieno(2,3-b)pyridin-3- amine.
  • methyl- or ethyl-hydrazine in solution to form 1-methyl- or 1-ethyl-1 H-pyrazolo(3',4':4,5)thieno(2,3-b)pyridin-3- amine.
  • the 3-amine-substituted product (VII) is acylated to convert the amine group to an appropriate amide derivative (VIII).
  • the amine can be acylated with carboxylic acid chlorides, bromides, anhydrides or esters using any of several standard procedures which are well known in the art.
  • Reaction (7) can be carried out in an inert organic solvent, such as methylene chloride, tetrahydrofuran, or dimethylformamide, or without added solvent, using the acylating agent as solvent such as acetic anhydride; the reaction temperature is not critical and can range between 0°C and the boiling point of the solvent or reaction mixture.
  • the use of an acid acceptor such as pyridine is preferred when Reaction (7) is carried out with a carboxylic acid halide.
  • X is a halogen (Cl, Br or I) and R b is an alkyl group which is ethyl or tert-butyl.
  • Reaction (8) is a nucleophilic displacement by thiolate on readily available chloronicotinic acid IX.
  • IX can be alkylated and esterified in one step (Reaction (9)) by treatment with ICH 2 CN, CICH 2 CN/KI or BrCH 2 CN under basic conditions, preferably KHC0 3 .
  • Reaction (9) is novel and labor-saving in that both the alkylation and esterification of X is carried out in one reaction step.
  • the cyclization step, Reaction (10) is straight forward, giving the readily isolated potassium oxide XII.
  • the hydrobromide salt was suspended in 550 ml of ethanol and the mixture heated to 45°C. A solution of 22.0 g of potassium hydroxide in 400 ml of ethanol was added and the reaction was stirred several hours at room temperature. The potassium salt of 3-bromothieno(2,3-b)pyridine-2-carboxylic acid was collected by filtration and dried overnight at 80°C under vacuum to give 44.0 g of product.
  • the potassium salt (42.4 g) was suspended in 650 ml of dry benzene and 30.0 g of oxalyl chloride was added dropwise. The reaction mixture was stirred and heated at reflux for one hour. Excess oxalyl chloride was removed by distillation at atmospheric pressure and the hot pot residue was added to a stirred mixture of 130 ml of concentrated ammonium hydroxide and ice. The precipitated 3-bromothieno(2,3-b)pyridine-2-carboxamide was collected by filtration and dried overnight at 80°C under vacuum to give 23.0 g of product, m.p. 266-268°C.
  • Treatment for individual infections may be oral or intranasal; however, oral treatment is the preferred method.
  • An oral dose range using tablets or capsules, of 2 to 50 mg/kg/dose with doses given as frequently as every 4 hours or as little as once a day, is the suggested regimen of dosing.
  • Pharmaceutical preparations of sustained release compositions can also be used as oral dosage forms.
  • effective methods include administration by intranasal drops, by nebulizer, or aerosol of useful droplet size.
  • An acceptable range of concentrations is between 0.1 mg/ml and 20 mg/ml, with a preferred range between 0.1 and 2.0 mg/ml.
  • Rhinovirus-sensitive HeLa cells are grown to confluent monolayers and infected with 2 J. Gwaltney, J. O. Hendley and P. Wenzel, N. Engl. J. Med., 288 1361 (1973). , 3 Fiala, M., Plaque Formation by 55 Rhinovirus Serotypes, Appl. Microbiol. 16: 1445 (1968). approximately 100 rhinovirus particles and subsequently covered with an agar-containing medium having varying concentrations of the test chemical. After 3 to 4 days of incubation at 34°C, the agar is removed and the plates stained with crystal violet. The amount of inhibition is determined by the reduction in the number of plaques in the cell layer, the minimum inhibitory compositions (MIC) being that concentration of compound required to completely suppress plaque formation.
  • MIC minimum inhibitory compositions
  • Example 1 The compound 2,2-diethyl-N-[1-methyl-1H-pyrazolo(3',4':4,5)thieno(2,3-b)pyridin-3-yl]butanamide (Example 1) was micronized to 2 microns or smaller particle size and suspended in distilled water at series dilutions from 50 ⁇ g/ml to 0.4 fl g/ml. The results obtained from testing against three rhinovirus strains are shown in Table 4. These results show that the test compound was 100% effective at preventing multiplication of rhinovirus at very low concentration.
  • the compounds of this invention may be employed in useful pharmaceutical compositions such as oral dosage forms, e.g. tablets, hard gelatin capsules, soft gelatin capsules and aqueous suspensions, and intranasal drops.
  • oral dosage forms e.g. tablets, hard gelatin capsules, soft gelatin capsules and aqueous suspensions, and intranasal drops.
  • the compounds of this invention will have a therapeutic dose range in man from 2.0 to 300 mg/kg/day.
  • the dosage forms described below are designed to deliver this therapeutic dose.
  • the amount of the compound of Example 1 in the lung tissue at each of these times was determined using a liquid chromatography assay, specific for the unchanged compound.
  • the results in Table 5 show that the level of compound present in the lung tissue, expressed as micrograms of compound per gram of lung, exceeded the in vitro antirhinovirus MIC (approximately 0.5 ⁇ g/mI) for at least 2 hours after the compound was administered.
  • Hard gelatin capsules can be prepared by filling standard two-piece hard gelatin capsules with the following mixture using conventional encapsulating equipment:
  • the following mixture is prepared and injected in gelatin by means of a positive displacement pump to form- soft gelatin capsules; the capsules are washed in petroleum ether and dried.
  • Tablets can be prepared by conventional procedures so that each tablet will contain:
  • An aqueous suspension for oral administration is prepared so that each 5 ml. contains:
  • effective methods include administration by intranasal drops, by nebulizer or aerosol.
  • An acceptable range of concentrations is between 0.1 mg/ml and 20 mg/ml, with a preferred range between 1.0 and 2.0 mg/ml. The following examples are designed to deliver this effective dose.
  • the compounds of this invention may be employed in useful pharmaceutical compositions such as hand disinfectants, e.g. lotion or rinse. Used topically, the compounds of this invention will have a therapeutic range from 0.1% to 10% in suitable carrier. The dosage forms described below are designed to deliver this therapeutic dose.
  • a medicated rinse can be prepared by mixing the following ingredients:
  • a medicated lotion can be prepared by mixing the following ingredients:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (12)

1. Un composé répondant à la formule:
Figure imgb0047
dans laquelle
R, est un groupe méthyle ou éthyle,
R2 est choisi parmi les groupes cyclohexyle, benzyle, 3-pyridyle, 1-adamantyle, halogénoalkyle en C2 à C5 portant 1 à 3 substituants halogènes en position autre que α relativement au groupe carbonvle et les groupes
Figure imgb0048
dans lesquels
X représente H, F ou Cl,
R3 et R4 représentent indépendamment H ou un groupe alkyle en C, à C3, et
R5 représente H ou un groupe alkyle en C1 à C5, ainsi que leurs sels d'addition d'acides pharmaceutiquement acceptables.
2. Un composé selon la revendication 1, dans lequel R, est un groupe méthyle.
3. Un composé selon la revendication 1, dans lequel R2 est un groupe 3-pyridyle.
4. Un composé selon la revendication 1, dans lequel R2 est un groupe halogénoalkyle en C, à C5 contenant 1 à 3 substituants halogènes et l'halogène est le chlore.
5. Un composé selon la revendication 1, dans lequel R2 est un groupement
Figure imgb0049
dans lequel R3 et R4 sont indépendamment des groupes alkyle en C, à C3 et R5 est H ou un groupe alkyle en C1 à C5.
6. Un composé selon la revendication 5, dans lequel R3, R4 et R5 sont des groupes méthyle.
7. Un composé selon la revendication 5, dans lequel R3, R4 et R5 sont des groupes éthyle.
8. Un composé selon la revendication 5, dans lequel R3 et R4 sont des groupes éthyle et Rs est H.
9. Le composé 2,2 - diéthyl - N - [1 - méthyl - 1H - pyrazolo(3',4.':4,5)thiénol2.3 - b)-pyridin - 3 - yl]butanamide selon la revendication 1.
10. Le composé 2 - éthyl - N - [1 - méthyl - 1H - pyrazolo(3',4':4,5)thiéno(2.3 - bipyridin - 3 - yl]hexanamide selon la revendication 1.
11. Une composition pharmaceutique comprenant un véhicule pharmaceutiquement approprié et un composé selon l'une quelconque des revendication 1 à 10, en une quantité suffisante pour la prophylaxie et le traitement de l'infection par rhinovirus chez les mammifères.
12. Procédé de synthèse d'un composé selon la revendication 1, consistant à faire reagir un composé de la formule:
Figure imgb0050
avec un composé carboxylique répondant à la formule
Figure imgb0051
où
Z est choisi parmi le chlore, le brome,
Figure imgb0052
R est un groupe alkyle en C1 à C3,
R1 est un groupe méthyle ou éthyle, et
R2 est choisi parmi les groupes cyclohexyle, benzyle, 3-pyridyle, 1-adamantyle
Figure imgb0053
en C2 à C5 portant 1 à 3 substituants halogènes en position autre que a relativement au groupe carbonyle. et les groupes
Figure imgb0054
dans lesquels
X est H, CI ou F.
EP79100705A 1978-03-10 1979-03-08 N-(pyridothiénopyrazol) amides, procédé pour leur préparation et compositions pharmaceutiques les contenant Expired EP0004319B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US88525278A 1978-03-10 1978-03-10
US885252 1978-03-10
US970732 1978-12-21
US05/970,732 US4220776A (en) 1978-12-21 1978-12-21 N-(Pyridothienopyrazol)amides

Publications (2)

Publication Number Publication Date
EP0004319A1 EP0004319A1 (fr) 1979-10-03
EP0004319B1 true EP0004319B1 (fr) 1981-08-05

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Country Status (18)

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EP (1) EP0004319B1 (fr)
JP (1) JPS54145698A (fr)
AR (1) AR221612A1 (fr)
AT (1) AT369370B (fr)
AU (1) AU522953B2 (fr)
CA (1) CA1114372A (fr)
DE (1) DE2960549D1 (fr)
DK (1) DK28979A (fr)
ES (1) ES478502A1 (fr)
FI (1) FI790818A (fr)
GR (1) GR66657B (fr)
HU (1) HU179006B (fr)
IL (1) IL56828A (fr)
NO (1) NO790778L (fr)
NZ (1) NZ189870A (fr)
PH (1) PH14896A (fr)
PT (1) PT69319A (fr)
SU (1) SU745368A3 (fr)

Also Published As

Publication number Publication date
IL56828A0 (en) 1979-05-31
ES478502A1 (es) 1980-07-01
NO790778L (no) 1979-09-11
FI790818A (fi) 1979-09-11
HU179006B (en) 1982-08-28
PT69319A (en) 1979-04-01
JPS54145698A (en) 1979-11-14
DK28979A (da) 1979-09-11
ATA179679A (de) 1982-05-15
DE2960549D1 (en) 1981-11-05
IL56828A (en) 1981-12-31
AT369370B (de) 1982-12-27
EP0004319A1 (fr) 1979-10-03
AR221612A1 (es) 1981-02-27
NZ189870A (en) 1981-07-13
AU522953B2 (en) 1982-07-01
SU745368A3 (ru) 1980-06-30
AU4488179A (en) 1979-09-13
PH14896A (en) 1982-01-08
CA1114372A (fr) 1981-12-15
GR66657B (fr) 1981-04-07

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